We are studying neurological disorders caused by deficiency of the signaling lipid PI(3,5)P2 (phosphatidylinositol-3,5-bisphosphate). PI(3,5)P2 is localized on membranes of the endolysosomal system. PI(3,5)P2 is generated by a complex including the kinase PIKFYVE, the scaffold protein VAC14, and the phosphatase FIG4 (Jin et al 2008). We demonstrated that mutations of FIG4 are responsible for the human neurological disorders Charcot-Marie-Tooth type 4J (CMT4J), Yunis-Varon syndrome, and polymicrogyria (Chow et al., 2007; Campeau et al., 2013; Baulac et al., 2014). Individuals with CMT4J and polymicrogyria exhibit variability in disease severity from early childhood to adulthood (Nicholson et al., 2011; Ben Cheikh BO et al., 2009). Variable severity is mimicked in mouse models with different strain backgrounds. Mice null for Fig4 and those homozygous for the Vac14 substitution L156R display early lethality on strain C57BL/6J but extended survival on strain C3HeB/FeJ. Our unique collection of mouse models of PI(3,5)P2 deficiency will be used to investigate this difference, using linkage and QTL analysis to elucidate the genetic architecture of the survival trait, to identify shared modifiers affecting survival of both Fig4 an Vac14 mutants. Future work will identify the responsible genes and target pathways for treatment of the human disorders.